COMMENTARY

Contrast Media Reactions Pose Serious Risk of Nephropathy

Joanna M. Pangilinan, PharmD, BCOP

Disclosures

August 25, 2008

Introduction

Contrast media are administered intravascularly to improve tissue visualization during diagnostic imaging (eg, computed tomography) and during certain procedures (eg, percutaneous transluminal coronary angioplasty).[1] Tens of millions of radiologic examinations using iodinated contrast media are performed each year.[1] Therefore, clinicians from all medical disciplines should be aware of the potential adverse effects associated with contrast media use.

Reactions to contrast media represent the third highest cause (11%) of hospital-acquired renal dysfunction.[2] Contrast-induced nephropathy (CIN), a serious risk of intravascular contrast use, occurs in 2% to 3% of patients who have undergone percutaneous coronary intervention (PCI).[3,4]

CIN is associated with both morbidity and mortality. Morbidity may include bleeding, sepsis, stroke, and respiratory failure.[4,5] Even small increases in serum creatinine (SCr) have been associated with increased length of hospital stays and inpatient mortality.[6] Patients in whom CIN developed after PCI had 15 times more myocardial infarction and/or vessel reocclusion.[3] A similar group of patients had 1-year and 5-year rates of myocardial infarction of 7% and 18.5%, compared with 3.8% and 10.5% in patients without renal failure.[4] Cardiac complications were a major reason for death in patients in whom acute renal failure developed following PCI.[3,4]

A cohort study found that patients in whom renal failure developed after contrast administration had an inpatient mortality risk of 34% compared with 7% in the control group.[5] This corresponded to an odds ratio of mortality of 5.5 after adjusting for comorbidity. Patients in whom renal failure developed after PCI had a higher estimated risk of death at 1 year (12.1%) and 5 years (44.6%) compared with those who did not develop renal failure (3.7% and 14.5%, respectively).[4]

Contemporary iodinated contrast media have evolved from a molecule containing 2 iodines[7] to 1 containing 6 iodines.[1,7] Osmolality, ionicity, and viscosity -- properties related to toxicity -- have been modified over time.[7] In current practice, the choice of a particular contrast medium depends on patient and procedural factors, current evidence, and guidelines.

Identifying Contrast-Induced Nephropathy

The true incidence of contrast-induced nephropathy is difficult to determine because no single definition of the condition exists.[8,9] Definitions often describe the change in SCr in absolute terms, such as an increase of 0.5 mg/dL, or in percentage terms, such as an increase of 25% from baseline. The definition usually incorporates a timeline for SCr increase (eg, within the first 24 hours following contrast administration) and its highest point (eg, within 5 days).[10]

Harjai and colleagues[11] compared the incidence of CIN after PCI using 4 different definitions. The definitions measured increase in baseline SCr using one of the following criteria: > 1.0 mg/dL,
> 0.5 mg/dL, > 25%, or 2-fold increase resulting in increase of > 2.0 mg/dL or requiring dialysis. The definitions that regularly predicted adverse clinical outcomes after PCI were increase in baseline SCr > 0.5 mg/dL and SCr > 25%.[11] Current CIN definitions used by organizations and committees are listed in Table 1 .

Interestingly, biomarkers other than creatinine are being studied as alternatives to detecting CIN. The concentration of cystatin C, a serum protein considered to be derived from nucleated cells,[14] may have promise as a measure of glomerular filtration rate (GFR) for detection of CIN.[15] Neutrophil-gelatinase-associated lipocalin, found in neutrophils and tissues,[16,17] and urinary interleukin-18[17] have shown promise in detecting early development of CIN.

Other causes of renal insufficiency must be considered when CIN is suspected. The differential diagnosis should include interstitial nephritis, cholesterol embolism, and dehydration.[9,18]

Pathophysiology

Recent reviews describe the complex pathophysiology of nephropathy caused by contrast
media.[8,10,19,20] Authors generally agree that the development of CIN is multifactorial. A simplified scenario involves an already decompensated kidney (estimated GFR < 60 mL/min/1.73m2) which, after administration of contrast media, undergoes an initial increase in renal blood flow due to vasoconstrictors such as endothelin and adenosine. Decreased blood flow follows, allowing contrast media to be directly nephrotoxic.[8,10]

Furthermore, production of nitric oxide, a protective vasodilator, may be compromised.[8,19] Subsequent stress may cause release of reactive oxygen species resulting in further renal
injury.[19,20] Continued research will be valuable for identifying at-risk patients and preventive measures.

Risk Factors

Patients with chronic kidney disease (CKD) have increased risk for nephropathy due to intravascular iodinated contrast use.[3,21,22] Patients with normal baseline kidney function have a low incidence of CIN (0.6%) while patients with mild or moderate CKD have a higher incidence (1.4% vs 6.4%, respectively).[3] However, many other risk factors have been identified in retrospective reviews.[21,22] Examples include diabetes mellitus, older age, left ventricular ejection fraction below 40%, and congestive heart failure.[22]

Risk factors considered "modifiable" include low effective circulatory volume, use of nephrotoxic agents, large dose (volume) of iodinated contrast, high osmolar contrast, ionic contrast, and short time interval between administration of 2 doses of contrast media.[22] Other risk factors have been identified[3,21,23], some described as "possible," "new," or "conflicting,"[23] making a comprehensive review beyond the scope of this article, In general, patient comorbidities, concurrent medications, demographics, and contrast requirements should be evaluated prior to the use of contrast media if possible.

Prevention Strategies

Due to the frequent use of contrast media (CM) and potential for adverse outcomes, many strategies have been evaluated for CIN prevention. Strategies include hydration protocols, forced diuresis, vasodilators, antioxidants, and extracorporeal contrast elimination.[24] In addition, studies have evaluated CIN incidence using different types of iodinated contrast[25,26] and alternatives to iodinated contrast (eg, gadolinium[27]).

Prophylactic strategies also depend on urgency of the procedure and patient risk factors.[28] Due to the vast research on CIN prophylaxis, a comprehensive review is beyond the scope of this article. Two strategies -- hydration and N-acetylcysteine administration -- will be discussed.

Volume expansion is a proven method for reducing the incidence of CIN. Solomon and colleagues first noted the protective effects of half-normal (0.45%) saline hydration in patients with chronic renal insufficiency receiving contrast in a small prospective trial.[29] Since then, normal saline (0.9%) hydration has generally replaced hypotonic hydration due to evidence suggesting benefit.[30] Use of sodium bicarbonate as isotonic replacement has yet to be established due to conflicting data.[31,32]

The CIN Consensus Working Panel recommends intravenous hydration (IV) for at-risk inpatients at 1-1.5 ml/kg/hour using isotonic hydration (eg, normal saline) starting 12 hours prior to a procedure and continuing for 6-24 hours after the procedure. Outpatients should receive IV hydration up to 3 hours prior to the procedure and up to 12 hours postprocedure.[24] Precautionary measures should be taken in patients with congestive heart failure if necessary.

Per the CIN Consensus Working Panel, current research has not determined the most effective hydration rate and duration. The role of oral hydration has yet to be elucidated.

The antioxidant N-acetylcysteine, indicated as an antidote for acetaminophen overdose and mucolytic,[33] has been widely studied off-label for CIN prevention. In less than a decade since the first published trial of this preventive strategy,[34] an explosion of trials and meta-analyses have been published, some with conflicting conclusions.

Vaitkus and colleagues reviewed 27 randomized controlled trials evaluating N-acetylcysteine for CIN prevention. They found that earlier studies usually concluded that this agent was highly efficacious, and results were published in journals with a higher impact factor. Later studies were equivalent in quality but described less positive results; they generally were published in journals with a lower impact factor.[35]

Other authors describe the presence of statistical and clinical heterogeneity in trials of N-acetylcysteine, leading to conflicting conclusions.[36,37] Biondi-Zoccai and colleagues evaluated systematic reviews and found that these meta-analyses were overlapping and differed in reporting quality and conclusions.[37]

As yet, no consensus exists regarding the efficacy of N-acetylcysteine for CIN prevention, although a recent study using cystatin C as a marker found such use to be favorable.[15] Another study found that the combination of N-acetylcysteine and sodium bicarbonate demonstrated better efficacy together than with N-acetylcysteine alone.[38]

Translating Guidelines Into Practice

The CIN Consensus Working Panel recommends further evaluation of theophylline/aminophylline, statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG CoA] reductase inhibitors), ascorbic acid, and prostaglandin E1 for CIN prevention.[24]

In the meantime, clinicians should refer to available guidelines and recommendations to assist with CIN risk evaluation, prevention, monitoring, and specific patient scenarios. Examples of organizational guidelines are listed in Table 2 .

Despite the wealth of knowledge and research regarding CIN, deficiencies exist in evidence-based practice. A survey of 509 European radiologists found variability in knowledge of CIN risk factors, its impact, and preventive measures.[43,44] While 72% believed that CIN increased morbidity, 56% did not believe that it increased mortality. Renal dysfunction, dehydration, and diabetes (97%, 90%, 89%, respectively) were identified as risk factors; other risk factors were identified less frequently (older age 26%, CM dose 30%, congestive heart failure 46%).[43]

About 9% of the respondents did not routinely identify at-risk patients and 16% were unaware that IV hydration is effective for CIN prevention. Of those who were aware, 59% used IV hydration and 52% used oral hydration in high-risk patients. The survey also detected variability in the volume of contrast media used in high-risk patients.[44] These results underscore the importance that evidence-based protocols are necessary to assist the clinician in identifying the at-risk patient and in using appropriate prophylaxis.[43,44]

Measures should be taken if a patient develops CIN. Solomon and Barrett recommend that clinicians monitor daily SCr measurements for inpatients. Agents that affect kidney function should be avoided while SCr is elevated (eg, contrast media and nephrotoxic medications). If possible, medications that interfere with GFR (eg, angiotensin-converting enzyme inhibitors) and medications excreted by glomerular filtration (eg, metformin) should be held. Clinicians should ensure that cardiovascular risk factors be minimized in these patients as they may have heightened risk for future adverse events.[45]

Conclusion

Clinicians will likely encounter patients at risk for CIN for years to come, due to an aging population with an increased incidence of diabetes and renal dysfunction. Many CIN guidelines and recommendations are available to assist the multidisciplinary team with patient risk evaluation and preventive strategies, monitoring, and clinical scenarios ( Table 2 ). Clinicians should keep abreast of organizational guidelines, institutional guidelines, and current literature consistently to best prevent the potentially serious renal effects of CM.

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